Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload–Induced Mitochondrial Dysfunction and Heart Failure

Abstract

Background Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Methods and Results Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure (HF) was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Mito-Keima, was transiently activated around 3–7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and HF after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on Day 7 after TAC partially rescued mitochondrial autophagy, and attenuated mitochondrial dysfunction and HF induced by pressure overload (PO). Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Conclusions Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to PO. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and HF, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during PO.

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…Conversely, the cardiomyocyte-specific overexpression of ATG7 reduced biochemical and functional biomarkers of the disease in this model, as did physical exercise (which is an established activator of autophagy) 114 . Consistent with this, autophagy activators — including (but not limited to) caloric restriction, physical exercise, rapamycin, <m>spermidine</m> and a peptide derived from the BECN1 region that interacts with the HIV-1 protein Nef (whose mechanism of action has not been characterized yet) — had beneficial effects in models of myocardial ischaemia reperfusion 115–117 , pressure overload-driven hypertrophy or heart failure 118–120 , and cardiac senescence 121 . Notably, the devices that are currently used in the clinic for <m>coronary angioplasty</m> generally deliver rapamycin 122 , although the underlying rationale resides in the antiproliferative activity of this drug 123 .…”

DLP1‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death

“…Studies demonstrated that suitable mitochondrial fission is required for damaged mitochondria before removal by mitophagy in mouse pancreatic β cells (Twig et al ., 2008). Besides, downregulation of DLP1 has been reported to prevent mitochondrial autophagy in mouse heart (Ikeda et al ., 2015; Shirakabe et al ., 2016). DLP1 has also been described to modulate mitophagy, possibly involving the interaction of DLP1 with the mitophagy receptor FUN14 domain‐containing 1 Pan troglodytes (FUNDC1) (Zuo et al ., 2014; Wu et al ., 2016).…”

New and revisited approaches to preserving the reperfused myocardium

“…The role of autophagy in cardiac remodelling is controversial, with numerous studies reporting evidence for a protective role 209,243,244 , an adverse role 220 , or both 199,245 . Autophagy has also been implicated in the pathological role of angiotensin II on hypertrophy 246 , but its role in this setting is somewhat controversial 247 , and might be related to a functional dichotomy of autophagy or the nonspecific criteria for defining upregulated autophagy.…”